Central Illustration

Abstract

Background Although previous observational studies have documented late luminal enlargement and expansive remodeling following implantation of a bioresorbable vascular scaffold (BVS), no comparison with metallic stents has been conducted in a randomized fashion.

Methods In the ABSORB II randomized trial, 383 lesions (n = 359) were investigated by intravenous ultrasound both post-procedure and at 3-year follow-up. According to vessel and lumen area changes over 3 years, we categorized 9 patterns of vessel remodeling that were beyond the reproducibility of lumen and vessel area measurements.

Conclusions Expansive vessel wall remodeling was more frequent and intense with the BVS than the metallic DES and could be determined by patient baseline characteristics and periprocedural factors. The clinical effect of the observed lumen and vessel remodeling must be investigated in further large clinical studies to optimize the clinical outcome of patients and lesions treated by bioresorbable scaffolds. (ABSORB II Randomized Controlled Trial; NCT01425281)

Intravascular ultrasound (IVUS) has been instrumental in the understanding of the atherosclerotic process and in the development of coronary interventional cardiology (1). Basically, IVUS defines 2 interfaces: 1) one between the flowing blood and the intima; and 2) one between the media and the adventitia. Therefore, multiple options of interaction exist among these 3 compartments, lumen, plaque-media, and adventitia. The relationship between lumen area (LA), plaque-media, and vessel area (VA) is the foundation of Glagov’s principle of compensatory expansive remodeling of the external elastic membrane (2). Considering the changes in these 3 compartments, there are, conceptually, 9 possibilities of expansive or constrictive remodeling, increase or decrease in plaque-media, and increase or decrease in LA (3). Fundamental to atherosclerosis progression and regression, these interactions are also essential as vessel wall reactions to the transient barotrauma of balloon angioplasty (4–7) and the permanent or transient “scaffolding” effect of either metallic stents (8) or bioresorbable scaffolds (9).

The advent of bioresorbable vascular scaffolds (BVS) has prompted us to analyze the short- and long-term effect of the bioresorbable scaffolds on vessel wall dynamics, including remodeling (10). It has been hypothesized that the potential for remodeling should be more prominent than the remodeling observed with metallic stents and should lead to late lumen enlargement (11). The ABSORB II trial did not meet its coprimary endpoints: superiority in vasomotion and noninferiority in angiographic late luminal loss following implantation of the Absorb drug-eluting BVS compared with the Xience metallic drug-eluting stent (DES) (Abbott Vascular, Santa Clara, California), but it has given us the opportunity to investigate, in the context of a randomized trial, the changes of long-term vessel wall morphometry after implantation of either bioresorbable scaffolds or metallic stents.

Methods

The ABSORB II trial was a prospective, single-blind, multicenter clinical trial that randomized patients to percutaneous coronary intervention (PCI) with placement of either Absorb bioresorbable scaffolds or Xience metallic stents in a 2:1 fashion. The trial design, the study devices, and the inclusion and exclusion criteria have been described in detail previously (12,13). As mandated by the protocol, all patients underwent documentary grayscale IVUS and backscattered radiofrequency (virtual histology [VH]) assessment before and after device implantation, as well as at 3-year follow-up. Clinical visits and blood sample analysis, including low-density lipoprotein cholesterol (LDL-C), were performed at 30 and 180 days and at 1, 2, and 3 years after the index procedure. The blood samples were analyzed by a central laboratory.

IVUS image acquisition and analysis

IVUS data were acquired with a 3.2-F, 45 MHz rotational IVUS catheter (Revolution 45 MHz, Volcano Corporation, Rancho Cordova, California) after intracoronary injection of 200 μg of nitroglycerin, at a pullback speed of 0.5 mm/s and a frame speed of 30 frames/s. All pullbacks were analyzed offline at 1-mm longitudinal intervals by an independent core laboratory (Cardialysis BV, Rotterdam, the Netherlands) using commercially available software (QIvus version 2.2, Medis, Leiden, the Netherlands).

The methods of quantitative IVUS have been previously published (1,12). Considering the difficulty in measuring neointima in the biodegraded scaffold at 3 years, to better compare the 2 devices, the intrascaffold-stent neointima was included in the metric “plaque-media = vessel area − lumen area.” The reference segments after device implantation were the 5-mm segments proximal and distal to the device. According to a previous study (14), relative range of interobserver reproducibility of measurement for lumen, plaque-media, and vessel cross-sectional areas based on 2 SD of their measurements were ±15%, ±22%, and ±12%, respectively. Specifically, expansive remodeling was defined as a relative change in mean VA >+12%, while constrictive remodeling was defined as a relative change in mean VA <−12%. According to these relative values of reproducibility, there were 9 theoretical patterns of vessel-lumen-plaque remodeling based on increase, no change, and decrease in each of the 3 parameters (Central Illustration) (3).

The pre-procedure target (“to-be-scaffolded/stented”) segments were defined by coregistration with post-procedural IVUS using identical landmarks, such as side branches and calcium locations. Matching was done using dedicated software (IvusOCTRegistration, Division of Image Processing, Leiden, the Netherlands) (15). Pre-procedural IVUS-VH analysis was performed within the target segments. Tissue compositions, derived from pre-procedural IVUS-VH analysis, were expressed in percentages, averaged for multiple plaque-media cross-sectional areas, and related to the different patterns of remodeling at follow-up (16).

Pre-procedural offline or online qualitative comparative analysis (QCA) for the sizing of the device was mandatory. The strategy of device deployment, with or without post-dilation, is described in detail in the protocol as well as the various parameters involved in device deployment (Online Appendix). The maximal diameter of the device/post-dilation balloon throughout the procedure was used for calculation of various balloon-artery ratios, with reference lumen diameter defined either by IVUS using a circular model, as the average of 5-mm segments proximal and distal to the device segment (17), or by QCA using the interpolated method (Online Table 1).

The definitions of expansion index, asymmetry index, eccentricity index, and deployment index are reported in the Online Appendix(15,18–20).

Overall substudy objectives

The primary objective of this study was to elucidate differences in remodeling patterns following BVS or DES implantation. First, differences in mean lumen, vessel, and plaque area changes were to be documented and the various patterns of remodeling established. Second, exploratory analysis of remodeling predictors, such as tissue composition analyzed by IVUS-VH and balloon-artery ratio, was performed. Finally, independent predictors for expansive remodeling were determined from multivariate analysis.

Statistical analysis

Categorical variables are presented as counts and percentages. Continuous variables are presented as mean ± SD or median (interquartile range), as appropriate. A p value <0.05 was considered statistically significant. Categorical variables were compared using chi-square statistics or Fisher exact test. Continuous variables between post-procedure and 3-year follow-up were compared with paired Student t test, and those between groups were compared with independent Student t test or analysis of variance with application of Bonferroni correction. In case of target lesion revascularization, the IVUS documentation prior to the treatment was carried forward and included in the statistical analysis of the 3-year results. The Pearson correlation coefficient was used to evaluate the strength and direction of the linear relationship between 2 parameters. Receiver-operating characteristic (ROC) analyses were performed to compare diagnostic ability, and Youden index was used to derive the cutoff point. Multivariate logistic regression analysis was performed to find independent determinants of vessel remodeling. The models were constructed using significant variables (p < 0.05) of univariate analyses. Statistical analyses were performed with SPSS version 24.0.0.1 (IBM, Armonk, New York).

Results

In the ABSORB II trial, of 546 lesions (n = 501) analyzed at baseline, 247 lesions (n = 233) in the BVS arm and 136 lesions (n = 126) in the DES arm had both post-procedure and 3-year follow-up IVUS images (Figure 1). Among lesions with paired post-procedure and 3-year follow-up IVUS, pre-procedural IVUS was available for 237 lesions in the BVS arm and 129 lesions in the DES arm, whereas pre-procedural IVUS-VH was available in 224 and 123 lesions, respectively. Baseline clinical, lesion, and procedural characteristics in patients and lesions with paired post-procedural and 3-year IVUS were well balanced between both arms (Table 1). In terms of procedural characteristics, the maximal pressure during device implantation or post-dilation, nominal and expected diameter of post-dilation balloon, and measured diameter of device and post-dilation balloon were significantly higher in the DES arm than in the BVS arm.

The absolute and relative changes in mean LA, plaque-media area, and VA between post-procedure and 3-year follow-up are tabulated in Table 2 (IVUS parameters post-procedure and at 3-year follow-up are provided in Online Table 2). The relative changes in mean VA, LA, and plaque-media area were significantly different for the 2 arms (Figure 2).

A total of 9 patterns of remodeling were characterized; reference lines indicate ±12% relative change in mean VA and ±15% relative change in mean LA (boundaries for interobserver reproducibility). Data are counts (%). Absolute values in each group are tabulated in Online Table 3. To facilitate the understanding of complex relationships among relative changes of mean vessel, lumen, and plaque area, 3-dimensional scatter plots were created (Online Videos 1 and 2). *p value for chi-square test. Abbreviations as in Figure 2.

Based on the boundaries of interobserver reproducibility of area measurements, we categorized 9 patterns of remodeling per relative changes in mean LA and mean VA (Central Illustration, Figure 3). The IVUS parameters post-procedure and at 3 years within each group are provided in Online Table 3.

The lesion subset groups are labeled A through I (Figure 3). In the BVS arm, groups B and C showed an increase in mean LA that was beyond interobserver reproducibility. In group B, the increase in mean LA was partially due to a small decrease in plaque-media area and plaque burden. Group C consisted of cases with late lumen enlargement associated with expansive remodeling that exceeded the increase in plaque-media area, resulting in a plaque burden decrease. Group E, with the largest number of observations, consisted of lesions that did not show any change beyond the interobserver reproducibility for VA and LA measurements. Group F displayed an increase in plaque-media, which was largely compensated by an expansive remodeling of the vessel, so that the lumen area showed minor changes, but plaque burden increased. Group G exhibited a decrease in mean LA mainly resulting from constrictive remodeling. Finally, group H comprised lesions with a decrease in mean LA resulting from an increase in mean plaque-media area, not compensated by expansive remodeling.

In the DES arm (Figure 3), the large majority of lesions (group E) did not exhibit any change in LA or VA beyond the interobserver reproducibility. The second group in terms of number (group F) was represented by stented lesions that exhibited some degree of VA increase without LA decrease (no intrastent neointimal hyperplasia). Group H was characterized by an LA decrease due to an increase in intrastent neointima not associated with VA increase. The other groups contained fewer than 5 patients.

In both arms, there were no patients with expansive remodeling and a decrease in lumen dimensions or constrictive remodeling with an increase in lumen dimensions (group A or I). In comparing proportions of each remodeling subset in the 2 arms (Table 3), expansive remodeling and either lumen enlargement or lumen reduction were more frequent in the BVS arm versus the DES arm, whereas frequency of constrictive remodeling did not differ. Late acquired malapposition was documented in 6 lesions of the BVS arm and was associated with LA increase (Online Table 4). One late acquired malapposition was observed in BVS group E.

Proportions of pre-procedural VH composition (average percentage of each tissue component in plaque-media areas) according to vessel remodeling patterns at follow-up are shown in Table 4 and Figure 4. In the BVS arm, there were no significant differences in the proportion of fibrous, fibrofatty tissue and dense calcium between the various vessel remodeling patterns; the proportion with a necrotic core was significantly less in the constrictive remodeling group, but was higher in the expansive remodeling group than in the group without vessel remodeling. In the DES arm, there were no significant differences in IVUS-VH composition for each remodeling group. ROC analysis of the proportion of necrotic core that predicted expansive remodeling in the BVS cases showed an area under the curve of 0.63 (95% CI: 0.55 to 0.71; p = 0.004) with a cutoff value of 16.7% (sensitivity 61.0%, specificity 61.8%). ROC analysis performed in the DES group did not show significance (p = 0.255).

The nominal, expected, or measured value of the maximal balloon diameter and balloon-artery ratios for the 3 categories of vessel remodeling (constrictive, no change in VA, expansive) are shown in Table 5 and Figure 5. Overall, the balloon diameters, either nominal or expected or measured by QCA (mean or minimal), failed to show any relationships with the development of constrictive or expansive remodeling in either group. However, increased balloon-artery ratios were associated with expansive remodeling in the BVS arm, in particular when nominal and expected balloon-artery ratios were used; only the QCA-measured balloon-artery ratio was associated with expansive remodeling in the DES arm.

The ROC analysis of expected balloon-artery ratio, among other balloon-artery ratios, showed the largest area under the curve (0.69; 95% CI: 0.61 to 0.77; p < 0.001) with a cutoff point of 1.25 (sensitivity 61.0%, specificity 75.3%) for prediction of expansive remodeling in the BVS arm. ROC analysis of expected balloon-artery ratio performed in the DES group did not show significance (p = 0.174).

Predictors for expansive remodeling (n = 87 lesions, 22.7%) were analyzed by multivariate logistic regression analysis, whereas predictors for constrictive remodeling were not investigated due to the limited number of lesions with constrictive remodeling (n = 18 lesions, 4.7%). Online Table 5 shows the result of univariate analysis for predictors of expansive remodeling. Subsequent multivariate analysis (Table 6) identified that BVS implantation, female sex, balloon-artery ratio by maximal expected diameter of balloon throughout procedure >1.25, expansion index ≥0.8, previous PCI, and higher mean LDL-C over 3 years were independent predictors for expansive remodeling. When the multivariate model was applied to the BVS population only, pre-procedural proportion of necrotic core >16.7% became significant. The multivariate analysis of the DES arm is not formally reported due to the small number of lesions showing expansive remodeling (16 lesions, 11.8%). However, the effect of the device type (p value for interaction) was not significantly different for each independent determinant of expansive remodeling identified by the multivariate analysis, despite some trends that might become significant in a larger sample size population (Figure 6).

At a single time point in a post-mortem study, Glagov et al. (2) reported that the LA was not decreased in relation to any plaque burden increase for values between 0% and 40%, but beyond that threshold, the compensatory expansive remodeling was no longer operational. In fact, very few lesions investigated in the present study had plaque burden <40% (Online Table 2); however, the relationship between LA and plaque burden >40% was consistent with Glagov’s theorem (Figure 7). In our serial analysis, taking into account the measurement variability of the plaque burden metrics, true plaque burden regression could not be documented in both arms, whereas plaque burden increase was observed in 12.1% in the BVS arm and 4.5% in the DES arm. However, the slope of the relationship between plaque burden and LA was 2-fold steeper in the scaffold arm (0.16) when compared to the DES arm (0.08), exemplifying the remodeling capability of the scaffolds.

Vascular response after intervention and function of scaffolding

In the era of balloon angioplasty, restenosis was caused mainly by constrictive remodeling (4). In a study using serial IVUS after angioplasty or directional coronary atherectomy, expansive remodeling was observed up to 1 month, but luminal reduction prevailed from 1 to 6 months, mainly due to negative remodeling (5,6). Between 6 months and 5 years, most patients have luminal enlargement after balloon angioplasty (7).

Bare-metal stents were found to prevent constrictive remodeling, but generated intrastent neointimal hyperplasia resulting in some cases of in-stent restenosis (8). Antiproliferative drug-eluting metallic stents are effective to reduce intrastent neointimal hyperplasia (21). With early-generation DES, positive remodeling leading to late acquired malapposition could occur, whereas this phenomenon is almost absent in newer-generation DES (22).

Drug-eluting bioresorbable scaffolds prevent constrictive remodeling in the first 6 months following implantation, but after the loss of their mechanical integrity, they allow expansive remodeling modulated by predictors described in the following text (23–25).

In contrast to the current study, the mean LA observed by optical coherent tomography in ABSORB cohort B at 3 years was stable after the initial decrease at 6 months (10). However, due to the shorter penetration depth, optical coherent tomography could not evaluate VA and remodeling as IVUS was able to in this study.

Predictors for expansive remodeling

In the present study, BVS implantation was an independent predictor for expansive remodeling. In previous observational studies, it has been documented that the mechanical support of scaffolds is lost 6 to 12 months after implantation (23) and that vessel and scaffold can potentially enlarge subsequently. In the preclinical study by Otsuka et al. (26), BVS implantation had a greater inflammation score than the metallic stents studied here; the scaffolds exhibited expansive remodeling 12 months after implantation, which was paralleled by LA enlargement, whereas metallic stents showed minimal change in vessel size. Considering the interaction between polymer degradation and inflammatory response (27), polymer absorption may promote inflammation and consecutive expansive remodeling after BVS implantation. However, the resorption of lactic acid is not a sole driver, if at all. Loss in scaffold structures (late structural discontinuity) and recovery of pulsatility might also contribute to remodeling mediated by inflammation (28,29) and may play a major role in late lumen enlargement and vessel remodeling. Besides the inflammatory response, another determinant of remodeling might be shear stress, whose influence is currently being investigated (30).

Female sex was also an independent predictor for expansive remodeling in the current study. In an IVUS substudy of the WISE (Women’s Ischemia Syndrome Evaluation) study, there was a high prevalence of atherosclerosis with positive remodeling and preserved lumen size (31). Considering that estrogen has anti-inflammatory effects, the pro-inflammatory status after menopause might promote expansive remodeling (32).

Among the balloon-artery ratios investigated, the ratio calculated with the expected balloon diameter had the best predictive value, probably because the parameter also incorporates the inflation pressure. The expected balloon diameter concept has been appropriately criticized because this parameter was evaluated in vitro, in the absence of any constraining force, such as a calcified or fibrotic wall; however, in this study, the statistical analysis based on a sensitivity-specificity indicator led us to discover that an expected balloon-artery ratio >1.25 was an independent procedural parameter predicting an expansive remodeling process in a large-scale clinical study. A high balloon-artery ratio resulted in vascular injury, which has been reported to induce expansive remodeling (33) through macrophage infiltration and matrix metalloproteinase increase (34). Also, the relationship between expansion index and vessel remodeling must rely on the same pathophysiological principle.

Higher LDL-C and necrotic core have previously been reported as predictors of expansive remodeling (35–37). Higher LDL-C level can increase necrotic core, oxidize lipid pool in vessel walls, and induce inflammatory responses involving metalloproteinases that promote vessel enlargement (38,39). The concomitant presence of a pre-existing inflammatory process (necrotic core) and the inflammatory process specifically related to the bioabsorption of the polymer may lead to longer and stronger inflammation-inducing expansive remodeling (26,40).

Study limitations

The major limitation of this study is the intravascular character of the investigation; whenever the IVUS catheter did not or could not cross the scaffolded or stented area, IVUS data for serial assessment were not available, which could potentially bias the serial analysis of wall dynamics. Of 32 patients who had repeat target lesion revascularization, 18 had intravascular imaging before repeat treatment of their target lesion, whereas the remaining 14 were not assessed. The expected balloon-artery ratio was only available in 325 of 383 lesions (84.9%) due to the lack of IVUS-measured reference lumen diameter. The univariate predictive value of necrotic core for positive remodeling was weak according to the low area under the curve. However, the identified threshold emerged as an independent predictor in the multivariate analysis in conjunction with other parameters. Multivariate analyses for constrictive remodeling could not be performed due to the limited number of lesions. At the present stage, the clinical significance of (expansive) remodeling with the BVS studied here is unclear due to the small number of patients enrolled as well as the small number of events reported.

Conclusions

In the ABSORB II trial, BVS use showed frequent dynamic vessel remodeling with larger increase in mean lumen and vessel area than the comparator DES. This vessel remodeling was determined by patient baseline characteristics and periprocedural factors including balloon-artery ratio and expansion index. The clinical effect of this observed lumen and vessel remodeling requires investigation in further large clinical studies.

Perspectives

COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Coronary lesions treated with bioresorbable scaffolds more frequently exhibit expansive remodeling than those treated with metallic stents. In addition, patient characteristics and procedural factors such as balloon-artery ratio and expansion index also influence vessel remodeling.

TRANSLATIONAL OUTLOOK: Additional research is needed to elucidate the relationship between dynamic vessel remodeling and clinical outcomes in patients undergoing percutaneous revascularization with these devices.

Appendix

Appendix

For an expanded Methods section and supplemental tables as well as supplemental videos and their legends, please see the online version of this article.

Footnotes

This study was funded by Abbott Vascular. Dr. Serruys has served as a member of the advisory board for Abbott Vascular. Dr. Chevalier has served as a consultant for Abbott Vascular. Dr. van der Schaaf has received institutional research grants from Abbott Vascular. Dr. Baumbach has received research support from Abbott Vascular. Dr. Smits has received research grants from Abbott Vascular and St. Jude Medical; and has received speaker fees from Abbott Vascular and Medinol. Dr. Gershlick has served on the advisory board of and received lecture fees and travel sponsorship from Abbott Vascular. Dr. Ormiston has served on the advisory boards of Boston Scientific and Abbott Vascular. Dr. Egred has received honoraria for proctorship from Abbott, Boston Scientific, Volcano, Biosensors, Vascular Perspectives, Vascular Solutions, and Merrill. Dr. Fajadet has received educational grants from Abbott, Boston Scientific, Medtronic, and Terumo. Dr. Lesiak has received honoraria as a speaker and/or advisory board member from Abbott Vascular, Boston Scientific, AstraZeneca, Biotronik, St. Jude Medical, Terumo, and Volcano. Dr. Windecker has received research grants to his institution from Bracco, Boston Scientific, and Terumo. Dr. Byrne has received lecture fees from B. Braun Melsungen AG, Biotronik, and Boston Scientific; and has received research grants to his institution from Boston Scientific and Heartflow. Dr. Räber has received speaker fees and institutional grants from Abbott, Biotronik, St. Jude Medical, and Sanofi/Regeneron. Dr. van Geuns has received a research grant from Abbott Vascular. Dr. Mintz has received honoraria or grant support from Boston Scientific, Volcano, and ACIST. Dr. Onuma has served as a member of the advisory board for Abbott Vascular; and has received speaker honoraria from Terumo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

References

(2001) American College of Cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS): a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol37:1478–1492.

(1999) Intravascular ultrasound assessment of the relation between early and late changes in arterial area and neointimal hyperplasia after percutaneous transluminal coronary angioplasty and directional coronary atherectomy. Am J Cardiol83:1518–1523.

(2010) Evaluation of the second generation of a bioresorbable everolimus drug-eluting vascular scaffold for treatment of de novo coronary artery stenosis: six-month clinical and imaging outcomes. Circulation122:2301–2312.

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